Established Proteasome Inhibitor Revitalizes CAR T-Cell Therapy in Multiple Myeloma

Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has transformed the treatment landscape for relapsed or refractory multiple myeloma (R/R MM), offering deep and durable responses in heavily pretreated populations.^1,2

However, relapse after CAR T-cell therapy remains a significant clinical challenge, often driven by antigen escape or downregulation of BCMA on malignant plasma cells. Emerging research suggests that an established proteasome inhibitor, carfilzomib (Kyprolis; Onyx Pharmaceuticals, Inc/Amgen Inc), may help restore or enhance CAR T-cell efficacy, offering a potential new strategy for patients who have exhausted standard options.³

BCMA: A Critical but Vulnerable Target

BCMA is a cornerstone target in MM immunotherapy due to its high expression on malignant plasma cells and limited expression on other tissues.¹

“BCMA is well suited as a target for CAR T therapy because it is highly specific to malignant plasma cells,” explained Florian Bassermann, director of the Department of Internal Medicine III at the Technical University of Munich University Hospital in Munich, Germany. “But cancer immunotherapy triggers rapid evolution inside the body.”³

Clinical studies of BCMA-targeted CAR T-cell therapies, including idecabtagene vicleucel (ide-cel, Abecma; Celgene Corporation/Bristol Myers Squibb) and ciltacabtagene autoleucel (cilta-cel, Carvykti; Janssen Biotech, Inc/Legend Biotech), have revealed remarkable response rates in R/R cases.^1,2 In the landmark KarMMa study (NCT03361748), findings revealed that ide-cel achieved an overall response rate (ORR) of 73% among heavily pretreated patients.¹

Similarly, data from the CARTITUDE-1 trial (NCT03548207) of cilta-cel showed an ORR of 97%, with a very high proportion of stringent complete responses.² However, following these treatments, a significant number of patients eventually relapse. Loss or downregulation of BCMA limits CAR T cells’ ability to recognize and eliminate malignant plasma cells. As a result, strategies that maintain or restore BCMA expression could meaningfully extend the durability of CAR T-cell therapy.

Implications for Sequencing and Combination Strategies

The possibility of combining or sequencing carfilzomib with CAR T-cell therapy introduces important considerations for oncology pharmacists. Carfilzomib’s established safety profile—including risks of cardiovascular toxicity, hypertension, and infusion-related reactions—necessitates careful patient selection and monitoring.⁴ Pharmacists play a central role in evaluating prior therapies, organ function, and comorbidities when considering retreatment strategies in the relapsed setting.

Importantly, investigators are exploring whether earlier integration of carfilzomib may further enhance CAR T-cell outcomes.

“We now want to investigate whether our findings hold up in larger studies,” added Bassermann. “We’re also exploring whether it might make sense to administer the drug right at the start of CAR T-cell therapy.”³

His team suspects that the newly discovered mechanism may also degrade other surface molecules, and, if so, it could help improve other forms of immunotherapy as well.

For pharmacists involved in cellular therapy programs, these findings underscore the importance of understanding not only the direct cytotoxic effects of established agents but also their potential immunologic interactions. Coordination across multidisciplinary teams, including hematologists, cellular therapy specialists, and pharmacists, will be essential to design optimal combination regimens and mitigate overlapping toxicities.

A New Chapter for Established Agents

As the MM treatment paradigm becomes increasingly complex—with proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, bispecific T-cell engagers, and CAR T-cell therapies—revisiting established agents in innovative combinations may unlock additional therapeutic potential.³ The concept that a long-standing drug such as carfilzomib could restore sensitivity to cutting-edge immunotherapy illustrates how mechanistic insights can reshape clinical strategy.

Although larger studies are needed to confirm durability, define predictive biomarkers, and clarify optimal timing, these early data provide a compelling rationale for further investigation. For patients facing relapse after CAR T-cell therapy, the repurposing of an established proteasome inhibitor may represent a promising step toward extending remission and improving long-term outcomes.

REFERENCES

1. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850

2. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8

3. Established cancer drug gives multiple myeloma immunotherapy new lease of life. Oncology Central. February 18, 2026. Accessed February 24, 2026. https://www.oncology-central.com/established-cancer-drug-gives-multiple-myeloma-immunotherapy-new-lease-of-life/

4. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817-2825. doi:10.1182/blood-2012-05-425934